US9550779B2 - Derivatives and methods of treating hepatitis B infections - Google Patents

Derivatives and methods of treating hepatitis B infections Download PDF

Info

Publication number
US9550779B2
US9550779B2 US14/984,654 US201514984654A US9550779B2 US 9550779 B2 US9550779 B2 US 9550779B2 US 201514984654 A US201514984654 A US 201514984654A US 9550779 B2 US9550779 B2 US 9550779B2
Authority
US
United States
Prior art keywords
alkyl
compound
umol
mixture
hbv
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US14/984,654
Other languages
English (en)
Other versions
US20160185779A1 (en
Inventor
George D. Hartman
Scott Kuduk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novira Therapeutics LLC
Original Assignee
Novira Therapeutics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novira Therapeutics LLC filed Critical Novira Therapeutics LLC
Priority to US14/984,654 priority Critical patent/US9550779B2/en
Assigned to NOVIRA THERAPEUTICS, INC. reassignment NOVIRA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HARTMAN, GEORGE D., KUDUK, SCOTT
Publication of US20160185779A1 publication Critical patent/US20160185779A1/en
Priority to US15/375,652 priority patent/US10077264B2/en
Application granted granted Critical
Publication of US9550779B2 publication Critical patent/US9550779B2/en
Priority to US16/024,954 priority patent/US10538519B2/en
Priority to US16/702,069 priority patent/US20200181142A1/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/29—Hepatitis virus
    • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10171—Demonstrated in vivo effect

Definitions

  • HBV infection chronic hepatitis B virus (HBV) infection is a significant global health problem, affecting over 5% of the world population (over 350 million people worldwide and 1.25 million individuals in the U.S.).
  • HBV-infected patients Despite the availability of a prophylactic HBV vaccine, the burden of chronic HBV infection continues to be a significant unmet worldwide medical problem, due to suboptimal treatment options and sustained rates of new infections in most parts of the developing world.
  • Current treatments do not provide a cure and are limited to only two classes of agents (interferon alpha and nucleoside analogues/inhibitors of the viral polymerase); drug resistance, low efficacy, and tolerability issues limit their impact.
  • the low cure rates of HBV are attributed at least in part to the fact that complete suppression of virus production is difficult to achieve with a single antiviral agent.
  • persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma.
  • Current therapy goals for HBV-infected patients are directed to reducing serum HBV DNA to low or undetectable levels, and to ultimately reducing or preventing the development of cirrhosis and hepatocellular carcinoma.
  • the compound of Formula I is a compound of Formula II:
  • the compound of Formula I is a compound of Formula III:
  • the compound of Formula I is a compound of Formula IV:
  • compositions comprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • a method of eradicating an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of reducing the viral load associated with an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of reducing reoccurrence of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • a method of reducing an adverse physiological impact of an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • a method of inducing remission of hepatic injury from an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • the methods provided herein can further comprise administering to the individual at least one additional therapeutic agent selected from the group consisting of an HBV polymerase inhibitor, immunomodulatory agents, pegylated interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and agents of distinct or unknown mechanism, and a combination thereof.
  • the methods provided herein allow for administering of the at least one additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.
  • the methods provided herein reduce the viral load in the individual to a greater extent or at a faster rate compared to the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and any combination thereof.
  • the methods provided herein cause a lower incidence of viral mutation and/or viral resistance than the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • the methods provided herein further comprise administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.
  • a method of treating an HBV infection in an individual in need thereof comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of HBV vaccine.
  • the methods provided herein further comprise monitoring the HBV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable.
  • compounds e.g., the compounds of Formulas I, II, III, or IV, or pharmaceutically acceptable salts thereof, that are useful in the treatment and prevention of HBV infection in subject.
  • these compounds may modulate or disrupt HBV assembly and other HBV core protein functions necessary for HBV replication or the generation of infectious particles, may inhibit the production of infectious virus particles or infection or may interact with HBV capsid to afford defective viral particles with greatly reduced infectivity or replication capacity.
  • the compounds provided herein may act as capsid assembly modulators.
  • the compounds provided herein have potent antiviral activity, exhibit favorable metabolic properties, tissue distribution, safety and pharmaceutical profiles, and are suitable for use in humans.
  • HBV capsid protein plays essential functions during the viral life cycle.
  • HBV capsid/core proteins form metastable viral particles or protein shells that protect the viral genome during intercellular passage, and also play a central role in viral replication processes, including genome encapsidation, genome replication, and virion morphogenesis and egress. Capsid structures also respond to environmental cues to allow un-coating after viral entry. Consistently, the appropriate timing of capsid assembly and dis-assembly, the appropriate capsid stability and the function of core protein have been found to be critical for viral infectivity.
  • HBV capsid proteins impose stringent evolutionary constraints on the viral capsid protein sequence, leading to the observed low sequence variability and high conservation. Consistently, mutations in HBV capsid that disrupt its assembly are lethal, and mutations that perturb capsid stability severely attenuate viral replication.
  • the high functional constraints on the multi-functional HBV core/capsid protein is consistent with a high sequence conservation, as many mutations are deleterious to function. Indeed, the core/capsid protein sequences are >90% identical across HBV genotypes and show only a small number of polymorphic residues. Resistance selection to HBV core/capsid protein binding compounds may therefore be difficult to select without large impacts on virus replication fitness.
  • the compounds provided herein are useful in HBV treatment by disrupting, accelerating, reducing, delaying and/or inhibiting normal viral capsid assembly and/or disassembly of immature or mature particles, thereby inducing aberrant capsid morphology and leading to antiviral effects such as disruption of virion assembly and/or disassembly, virion maturation, virus egress and/or infection of target cells.
  • a disruptor of capsid assembly interacts with mature or immature viral capsid to perturb the stability of the capsid, thus affecting assembly and/or disassembly.
  • a disruptor of capsid assembly perturbs protein folding and/or salt bridges required for stability, function and/or normal morphology of the viral capsid, thereby disrupting and/or accelerating capsid assembly and/or disassembly.
  • the compounds of the invention bind capsid and alter metabolism of cellular polyproteins and precursors, leading to abnormal accumulation of protein monomers and/or oligomers and/or abnormal particles, which causes cellular toxicity and death of infected cells.
  • the compounds provided herein cause failure of the formation of capsids of optimal stability, affecting efficient uncoating and/or disassembly of viruses (e.g., during infectivity).
  • the compounds provided herein disrupt and/or accelerate capsid assembly and/or disassembly when the capsid protein is immature. In another embodiment, the compounds provided herein disrupt and/or accelerate capsid assembly and/or disassembly when the capsid protein is mature. In yet another embodiment, the compounds provided herein disrupt and/or accelerate capsid assembly and/or disassembly during viral infectivity. In yet another embodiment, the disruption and/or acceleration of capsid assembly and/or disassembly attenuates HBV viral infectivity and/or reduces viral load. In yet another embodiment, disruption, acceleration, inhibition, delay and/or reduction of capsid assembly and/or disassembly eradicates the virus from the host organism. In yet another embodiment, eradication of the HBV from a host advantageously obviates the need for chronic long-term therapy and/or reduces the duration of long-term therapy.
  • the compounds described herein are suitable for monotherapy and are effective against natural or native HBV strains and against HBV strains resistant to currently known drugs. In another embodiment, the compounds described herein are suitable for use in combination therapy.
  • the compounds provided herein can be used in methods of modulating (e.g., inhibiting or disrupting) the activity, stability, function, and viral replication properties of HBV cccDNA.
  • the compounds of the invention can be used in methods of diminishing or preventing the formation of HBV cccDNA.
  • the compounds provided herein can be used in methods of modulating (e.g., inhibiting or disrupting) the activity of HBV cccDNA. In yet another embodiment, the compounds of the invention can be used in methods of diminishing the formation of HBV cccDNA.
  • the compounds provided herein can be used in methods of modulating, inhibiting, or disrupting the generation or release of HBV RNA particles from within the infected cell.
  • the total burden (or concentration) of HBV RNA particles is modulated.
  • the total burden of HBV RNA is diminished.
  • the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • capsid assembly modulator refers to a compound that disrupts or accelerates or inhibits or hinders or delays or reduces or modifies normal capsid assembly (e.g., during maturation) or normal capsid disassembly (e.g., during infectivity) or perturbs capsid stability, thereby inducing aberrant capsid morphology and function.
  • a capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing aberrant capsid morphology.
  • a capsid assembly modulator interacts (e.g.
  • a capsid assembly modulator causes a perturbation in structure or function of CA (e.g., ability of CA to assemble, disassemble, bind to a substrate, fold into a suitable conformation, or the like), which attenuates viral infectivity and/or is lethal to the virus.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has an HBV infection, a symptom of HBV infection or the potential to develop an HBV infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the HBV infection, the symptoms of HBV infection or the potential to develop an HBV infection.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • prevent means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
  • the term “patient,” “individual” or “subject” refers to a human or a non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the patient, subject or individual is human.
  • the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • composition refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C 1 -C 6 -alkyl means one to six carbon atoms) and includes straight, branched chain Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl.
  • Other examples of C 1 -C 6 -alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.
  • alkenyl denotes a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group.
  • Alkenyl groups e.g., C 2 -C 8 -alkenyl
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.
  • halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • haloalkyl refers to alkl radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • Haloalkyl embraces monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals.
  • haloalkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, and pentafluoroethyl.
  • cycloalkyl refers to a mono cyclic or polycyclic nonaromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom.
  • the cycloalkyl group is saturated or partially unsaturated.
  • the cycloalkyl group is fused with an aromatic ring.
  • Cycloalkyl groups include groups having 3 to 10 ring atoms (C 3 -C 10 -cycloalkyl), groups having 3 to 8 ring atoms (C 3 -C 8 -cycloalkyl), groups having 3 to 7 ring atoms (C 3 -C 7 -cycloalkyl), and groups having 3 to 6 ring atoms (C 3 -C 6 -cycloalkyl).
  • Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene.
  • Polycyclic cycloalkyls include adamantine and norbornane.
  • cycloalkyl includes “unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon carbon double bond or one carbon carbon triple bond.
  • heterocycloalkyl or “heterocyclyl” refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, S and N.
  • each heterocyclyl group has from 3 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Heterocyclyl substituents may be alternatively defined by the number of carbon atoms, e.g., C 2 -C 8 -heterocyclyl indicates the number of carbon atoms contained in the heterocyclic group without including the number of heteroatoms.
  • a C 2 -C 8 -heterocyclyl will include an additional one to four heteroatoms.
  • the heterocycloalkyl group is fused with an aromatic ring.
  • the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
  • the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.
  • An example of a 3-membered heterocyclyl group includes, and is not limited to, aziridine.
  • Examples of 4-membered heterocyclyl groups include, and are not limited to, azetidine and a beta lactam.
  • Examples of 5-membered heterocyclyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione.
  • Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine and piperazine.
  • heterocyclyl groups are:
  • heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide.
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized ⁇ (pi) electrons, where n is an integer.
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene.
  • aryl groups include phenyl, anthracyl, and naphthyl. Preferred examples are phenyl (e.g., C 6 -aryl) and biphenyl (e.g., C 12 -aryl).
  • aryl groups have from six to sixteen carbon atoms.
  • aryl groups have from six to twelve carbon atoms (e.g., C 6 -C 12 -aryl).
  • aryl groups have six carbon atoms (e.g., C 6 -aryl).
  • heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
  • Heteroaryl substituents may be defined by the number of carbon atoms, e.g., C 1 -C 9 -heteroaryl indicates the number of carbon atoms contained in the heteroaryl group without including the number of heteroatoms.
  • a C 1 -C 9 -heteroaryl will include an additional one to four heteroatoms.
  • a polycyclic heteroaryl may include one or more rings that are partially saturated.
  • Non-limiting examples of heteroaryls include:
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • Non-limiting examples of polycyclic heterocycles and heteroaryls include indolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (including, e.g., 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (including, e.g., 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • W 1 and W are each independently selected from N, NR a , and CR a , wherein one of W 1 and W is NR a ;
  • X is N or CR b ;
  • Y is selected from a bond, —C(O)—, and —SO 2 —;
  • Z is selected from —(CR 5 R 6 ) m —, —(CR 5 R 6 ) m O—, —(CR 5 R 6 ) m CR 5 ⁇ CR 5 —, —(CR 5 R 6 ) m —C 3 -C 6 -cycloalkylene-, and —(CR 5 R 6 ) m —NR 7 —;
  • R 1 is selected from C 6 -C 12 -aryl, C 1 -C 9 -heteroaryl, C 3 -C 8 -cycloalkyl, C 2 -C 8 -heterocyclyl, —OR c , C 1 -C 6 -alkyl, C(O)OR c , C(O)R c , C(O)NR d R e , NR d C(O)R e , —OC(O)R c , halo, and C 2 -C 8 -alkenyl, wherein alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6
  • R 2 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 3 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 4 is selected from C 1 -C 6 -alkyl, (CR 8 R 9 ) p —C 3 -C 8 -cycloalkyl, (CR 8 R 9 ) p —C 2 -C 8 -heterocyclyl, (CR 8 R 9 ) p —C 6 -C 12 -aryl, and (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R
  • R 5 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 4 and R 5 are optionally joined to form a ring
  • R 6 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 7 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 8 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 9 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R a is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R b is selected from H and C 1 -C 6 -alkyl
  • R c is selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, C 3 -C 8 -cycloalkyl, C 2 -C 8 -heterocyclyl, C 6 -C 12 -aryl, and C 1 -C 9 -heteroaryl;
  • R d is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R e is selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, C 3 -C 8 -cycloalkyl, C 2 -C 8 -heterocyclyl, C 6 -C 12 -aryl, C 1 -C 9 -heteroaryl, and —O—C 1 -C 6 -alkyl;
  • R d and R e are optionally joined to form a heterocyclic ring
  • R f is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl
  • n 0, 1, 2, 3, or 4;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, or 4.
  • W 1 and W are each independently selected from N, NR a , and CR a , wherein one of W 1 and W is NR a .
  • X is N or CR b ;
  • Y is selected from a bond, —C(O)—, and —SO 2 —;
  • Z is selected from —(CR 5 R 6 ) m —, —(CR 5 R 6 ) m O—, —(CR 5 R 6 ) m CR 5 ⁇ CR 5 —, —(CR 5 R 6 ) m —C 3 -C 6 -cycloalkylene-, and —(CR 5 R 6 ) m —NR 7 —;
  • R 1 is selected from C 6 -C 12 -aryl and C 1 -C 9 -heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H;
  • R 2 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 3 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 4 is selected from C 1 -C 6 -alkyl, (CR 8 R 9 ) p —C 3 -C 8 -cycloalkyl, (CR 8 R 9 ) p —C 2 -C 8 -heterocyclyl, (CR 8 R 9 ) p —C 6 -C 12 -aryl, and (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R
  • R 5 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 4 and R 5 are optionally joined to form a heterocyclic ring
  • R 6 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 7 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 8 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 9 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R a is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R b is selected from H and C 1 -C 6 -alkyl
  • R f is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl
  • n 0, 1, 2, 3, or 4;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, or 4.
  • W 1 and W are each independently selected from N, NR a , and CR a , wherein one of W 1 and W is NR a ;
  • X is N or CR b ;
  • Y is selected from a bond, —C(O)—, and —SO 2 —;
  • Z is selected from —(CR 5 R 6 ) m —, —(CR 5 R 6 ) m O—, —(CR 5 R 6 ) m CR 5 ⁇ CR 5 —, —(CR 5 R 6 ) m —C 3 -C 6 -cycloalkylene-, and —(CR 5 R 6 ) m —NR 7 —;
  • R 1 is selected from C 6 -C 12 -aryl and C 1 -C 9 -heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1 or 2 groups each independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)HH;
  • R 2 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 3 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 4 is selected from C 1 -C 6 -alkyl, (CR 8 R 9 ) p —C 3 -C 8 -cycloalkyl, (CR 8 R 9 ) p —C 2 -C 3 -heterocyclyl, (CR 8 R 9 ) p —C 6 -C 12 -aryl, and (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R
  • R 5 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 4 and R 5 are optionally joined to form a ring
  • R 6 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 7 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 8 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 9 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R a is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R b is selected from H and C 1 -C 6 -alkyl
  • R f is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl
  • n 0, 1, 2, 3, or 4;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, or 4.
  • W 1 is NR a and W is N or CR a . In a further embodiment, W 1 is NH.
  • W 1 is N or CR a and W is NR a .
  • X is N.
  • Y is —C(O)— or —SO 2 —.
  • Z is —(CR 5 R 6 ) m —, —(CR 5 R 6 ) m O—, or —(CR 5 R 6 ) m —NR 7 —.
  • n 0 or 1
  • R 5 is H, —OH, or C 1 -C 6 -alkyl
  • R 6 is H or C 1 -C 6 -alkyl
  • R 7 is H or C 1 -C 6 -alkyl.
  • R 1 is C 6 -aryl or C 1 -C 9 -heteroaryl wherein aryl and heteroaryl are optionally substituted with 1 or 2 groups independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H.
  • R 1 is C 6 -aryl, pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any of which are optionally substituted by 1 or 2 groups independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H.
  • each R 2 is independently selected from H, C 1 -C 6 -alkyl, or C 1 -C 6 -alkyl-OH. In a further embodiment of the compound of Formula I, each R 2 is independently selected from C 1 -C 6 -alkyl or H. In yet a further embodiment of the compound of Formula I, R 2 is H.
  • R 3 is H or C 1 -C 6 -alkyl.
  • R 4 is (CR 8 R 9 ) p —C 3 -C 8 -cycloalkyl, (CR 8 R 9 ) p —C 2 -C 5 -heterocyclyl, (CR 8 R 9 ) p —C 6 -C 12 -aryl, or (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R f , and C 1 -C
  • R 4 is (CR 8 R 9 ) p —C 6 -C 12 -aryl, or (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, wherein aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R f , and C 1 -C 6 -alkyl-OH.
  • p is 0 or 1;
  • R 8 is H, —OH, or C 1 -C 6 -alkyl
  • R 9 is H or C 1 -C 6 -alkyl.
  • n 1
  • X is N
  • Y is —C(O)—
  • Z is NR 7 ;
  • R 7 is H or C 1-4 -alkyl.
  • X is N
  • Y is —C(O)—
  • Z is NR 7 ;
  • R 7 is H or C 1-4 -alkyl
  • n 1.
  • Y is —C(O)— or —SO 2 —.
  • Z is —(CR 5 R 6 ) m —, —(CR 5 R 6 ) m O— or —(CR 5 R 6 ) m —NR 7 —.
  • n 0 or 1
  • R 5 is H, —OH, or C 1 -C 6 -alkyl
  • R 6 is H or C 1 -C 6 -alkyl
  • R 7 is H or C 1 -C 6 -alkyl.
  • R 1 is C 6 -C 12 -aryl or C 1 -C 9 -heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1 or 2 groups each independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H.
  • R 1 is C 6 -aryl, pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any of which are optionally substituted by 1 or 2 groups independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H.
  • each R 2 is independently selected from H, C 1 -C 6 -alkyl, or C 1 -C 6 -alkyl-OH. In a further embodiment of the compound of Formula II, each R 2 is independently selected from C 1 -C 6 -alkyl or H. In yet a further embodiment of the compound of Formula II, R 2 is H.
  • R 3 is H or C 1 -C 6 -alkyl. In a further embodiment, R 3 is H.
  • n 1
  • R 4 is (CR 8 R 9 ) p —C 3 -C 8 -cycloalkyl, (CR 8 R 9 ) p —C 2 -C 8 -heterocyclyl, (CR 8 R 9 ) p —C 6 -C 12 -aryl, or (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R f , and C 1 -
  • R 4 is (CR 8 R 9 ) p —C 6 -C 12 -aryl, or (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R f , and C 1 -C 6 -alkyl-OH.
  • Y is —C(O)—
  • Z is —(CR 5 R 6 ) m —, —(CR 5 R 6 ) m O— or —(CR 5 R 6 ) m —NR 7 —;
  • R 1 is C 6 -aryl, pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any of which are optionally substituted by 1 or 2 groups independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H each R 2 is independently selected from H, C 1 -C 6 -alkyl, or C 1 -C 6 -alkyl-OH and R 3 is H;
  • R 4 is (CR 8 R 9 ) p —C 6 -C 12 -aryl, or (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R f , and C 1 -C 6 -alkyl-OH;
  • R 5 is H, —OH, or C 1 -C 6 -alkyl
  • R 6 is H or C 1 -C 6 -alkyl
  • R 7 is H or C 1 -C 6 -alkyl
  • R 8 is, at each occurrence, independently selected from H, —OH, halo, and C 1 -C 6 -alkyl;
  • R 9 is, at each occurrence, independently selected from H, —OH, halo, and C 1 -C 6 -alkyl;
  • R f is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl
  • n 1 or 2;
  • n 1;
  • p 0, 1, or 2.
  • R 1 is C 6 -aryl, optionally substituted by —OH or halo.
  • R 1 is C 6 -aryl, optionally substituted with halo.
  • R 4 is (CR 8 R 9 ) p —C 6 -C 12 -aryl, or (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH.
  • p is 0 or 1;
  • R 8 is independently selected from H, —OH, and C 1 -C 6 -alkyl
  • R 9 is independently selected from H and C 1 -C 6 -alkyl.
  • n 1
  • Y is —C(O)—
  • Z is NR 7 ;
  • R 7 is H or C 1-4 -alkyl.
  • Y is —C(O)—
  • Z is NR 7 ;
  • R 7 is H or C 1-4 -alkyl
  • n 1.
  • Y is —C(O)— or —SO 2 —;
  • R 1 is C 6 -C 12 -aryl or C 1 -C 9 -heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1 or 2 groups each independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H;
  • R 2 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 3 is selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 4 is selected from (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl, (CR 8 R 9 ) p —C 6 -C 12 -aryl, and C 3 -C 3 -cycloalkyl wherein heteroaryl, aryl, and cycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, and C 3 -C 8 -cycloalkyl.
  • R 7 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 8 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 9 is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl
  • p 0, 1, 2, 3, or 4.
  • Y is —C(O)— or —SO 2 —;
  • R 1 is C 6 -aryl, pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any of which are optionally substituted by 1 or 2 groups independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H;
  • R 2 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 3 is selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 4 is selected from (CR 8 R 9 ) p —C 1 -C 9 -heteroaryl and (CR 8 R 9 ) p —C 6 -C 12 -aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH.
  • R 7 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 8 is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;
  • R 9 is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl
  • p 0, 1, 2, 3, or 4.
  • Y is —C(O)—.
  • R 1 is C 6 -aryl, or C 1 -C 9 -heteroaryl, wherein aryl or heteroaryl are optionally substituted by —OH, halo, C 1 -C 6 -alkyl, or —O—C 1 -C 6 -alkyl.
  • R 1 is C 6 -aryl, C 6 -aryl, pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, or pyridazinyl, any of which are optionally substituted by 1 or 2 groups independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, CN, and C(O)H.
  • R 1 is C 6 -aryl.
  • each R 2 is independently selected from H, C 1 -C 6 -alkyl, or C 1 -C 6 -alkyl-OH. In a further embodiment of the compound of Formula III, each R 2 is independently selected from C 1 -C 6 -alkyl or H. In yet a further embodiment of the compound of Formula III, R 2 is H.
  • R 3 is H or C 1 -C 6 -alkyl. In a further embodiment of the compound of Formula III, R 3 is H.
  • R 7 is H or C 1 -C 4 -alkyl. In a further embodiment, R 7 is H or —CH 3 . In yet another embodiment, R 7 is H.
  • R 4 is (CR 8 R 9 ) p —C 1 -C 5 -heteroaryl or (CR 8 R 9 ) p —C 6 -aryl, or C 3 -C 8 -cycloalkyl, wherein heteroaryl, aryl and cycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, CN, and C 1 -C 6 -alkyl;
  • R 8 is H or C 1 -C 6 -alkyl
  • R 9 is H or C 1 -C 6 -alkyl
  • p 0 or 1.
  • R 4 is (CR 8 R 9 ) p —C 1 -C 5 -heteroaryl or (CR 8 R 9 ) p —C 6 -aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, CN, and C 1 -C 6 -alkyl;
  • R 8 is H or C 1 -C 6 -alkyl
  • R 9 is H or C 1 -C 6 -alkyl
  • p 0 or 1.
  • R 4 is
  • R 4 is
  • R 4 is
  • Y is —C(O)— or —SO 2 —
  • n 0, 1, or 2.
  • Y is —C(O)—.
  • R 1 is C 6 -C 12 -aryl or C 1 -C 9 -heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1 or 2 groups each independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, and CN.
  • R 1 is C 6 -aryl optionally substituted by —OH or halo.
  • R 2 is H.
  • R 3 is H.
  • m is 1, R 5 is H or C 1 -C 6 -alkyl, R 6 is H or C 1 -C 6 -alkyl, and wherein R 5 and R 4 are optionally joined to form a ring.
  • m is 1; R 5 is C 1 -C 6 -alkyl; R 6 is H or C 1 -C 6 -alkyl; and R 5 and R 4 are optionally joined to form a ring.
  • R 4 is C 1 -C 6 -alkyl or (CR 8 R 9 ) p —C 6 -C 12 -aryl, wherein alkyl and aryl are optionally substituted with 1, 2, or 3, groups, each independently selected from —OH, halo, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, C(O)N(R f ) 2 , C(O)OR f , —OCH 2 C(O)OR f , —SO 2 R f , and C 1 -C 6 -alkyl-OH.
  • R 4 is
  • the compound of Formula III is selected from compounds shown in Table 2 and pharmaceutically acceptable salts thereof.
  • the compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration.
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomer is utilized as the therapeutic compound described herein.
  • compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
  • isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • reactive functional groups such as hydroxyl, amino, imino, thio or carboxy groups
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
  • each protective group is removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • the invention provides a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention also provides a method of eradicating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention also provides a method of reducing viral load associated with an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method of reducing reoccurrence of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention also provides a method of reducing an adverse physiological impact of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method of reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention also provides a method of inducing remission of hepatic injury from an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method of prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
  • the methods described herein further comprise administering at least one additional therapeutic agent selected from the group consisting of nucleotide/nucleoside analogs, entry inhibitors, fusion inhibitors, and any combination of these or other antiviral mechanisms.
  • at least one additional therapeutic agent selected from the group consisting of nucleotide/nucleoside analogs, entry inhibitors, fusion inhibitors, and any combination of these or other antiviral mechanisms.
  • the compound of the invention and the at least one additional therapeutic agent are co-formulated.
  • the compound of the invention and the at least one additional therapeutic agent are co-administered.
  • the individual is refractory to other therapeutic classes of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof).
  • HBV drugs e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof.
  • the method of the invention reduces viral load in an individual suffering from an HBV infection to a greater extent or at a faster rate compared to the extent that other therapeutic classes of HBV drugs reduce viral load in the individual.
  • the administering of a compound of the invention, or a pharmaceutically acceptable salt thereof allows for administering of the at least one additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.
  • the administering of a compound of the invention, or a pharmaceutically acceptable salt thereof reduces the viral load in the individual to a greater extent or at a faster rate compared to the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and any combination thereof.
  • the method of the invention reduces viral load in an individual suffering from an HBV infection, thus allowing lower doses or varying regimens of combination therapies to be used.
  • the method of the invention causes a lower incidence of viral mutation and/or viral resistance compared to other classes of HBV drugs, thereby allowing for long term therapy and minimizing the need for changes in treatment regimens.
  • the administering of a compound the invention, or a pharmaceutically acceptable salt thereof causes a lower incidence of viral mutation and/or viral resistance than the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • the method of the invention increases the seroconversion rate beyond that of current treatment regimens.
  • the method of the invention increases and/or normalizes and/or restores normal health, elicits full recovery of normal health, restores life expectancy, and/or resolves the viral infection in the individual in need thereof.
  • the method of the invention eliminates or decreases the number of HBV RNA particles that are released from HBV infected cells thus enhancing, prolonging, or increasing the therapeutic benefit of the compounds of the invention.
  • the method of the invention eradicates HBV from an individual infected with HBV, thereby obviating the need for long term and/or life-long treatment, or shortening the duration of treatment, and/or allowing for reduction in dosing of other antiviral agents.
  • the method of the invention further comprises monitoring the HBV viral load of the subject, and wherein the method is carried out for a period of time such that the HBV virus is undetectable.
  • provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula IV, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 2, or a pharmaceutically acceptable salt thereof.
  • the method can further comprise monitoring the HBV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable.
  • the compounds of the present invention are intended to be useful in combination with one or more additional compounds useful for treating HBV infection.
  • additional compounds may comprise compounds of the present invention or compounds known to treat, prevent, or reduce the symptoms or effects of HBV infection.
  • Such compounds include but are not limited to HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, reverse transcriptase inhibitor, immunomodulatory agents, a TLR-agonist, and other agents with distinct or unknown mechanisms that affect the HBV life cycle and/or affect the consequences of HBV infection.
  • the compounds of the invention may be used in combination with one or more drugs (or a salt thereof) selected from the group consisting of
  • HBV reverse transcriptase inhibitors and DNA and RNA polymerase inhibitors, including but not limited to lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-HBV), entecavir (Baraclude, Entavir), adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovir disoproxil fumarate (Viread, TDF or PMPA);
  • lamivudine 3TC, Zeffix, Heptovir, Epivir, and Epivir-HBV
  • entecavir Baraclude, Entavir
  • adefovir dipivoxil Hepsara, Preveon, bis-POM PMEA
  • tenofovir disoproxil fumarate Viread, TDF or PMPA
  • interferons including but not limited to interferon alpha (IFN- ⁇ ), interferon beta (IFN- ⁇ ), interferon lambda (IFN- ⁇ ), and interferon gamma (IFN- ⁇ );
  • capsid assembly modulators such as, but not limited to BAY 41-4109;
  • an immunomodulatory agent such as a TLR-agonist
  • agents of distinct or unknown mechanism such as but not limited to AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), AT-130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), and similar analogs.
  • the additional therapeutic agent is an interferon.
  • interferon or “IFN” refers to any member the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation, and modulate immune response. Human interferons are grouped into three classes; Type I, which include interferon-alpha (IFN- ⁇ ), interferon-beta (IFN- ⁇ ), and interferon-omega (IFN- ⁇ ), Type II, which includes interferon-gamma (IFN- ⁇ ), and Type III, which includes interferon-lambda (IFN- ⁇ ). Recombinant forms of interferons that have been developed and are commercially available are encompassed by the term “interferon” as used herein.
  • interferons such as chemically modified or mutated interferons
  • Chemically modified interferons include pegylated interferons and glycosylated interferons.
  • Examples of interferons also include, but are not limited to, interferon-alpha-2a, interferon-alpha-2b, interferon-alpha-n1, interferon-beta-1a, interferon-beta-1b, interferon-lamda-1, interferon-lamda-2, and interferon-lamda-3.
  • pegylated interferons include pegylated interferon-alpha-2a and pegylated interferons alpha-2b.
  • the compounds of Formula I, II, III, or IV can be administered in combination with an interferon selected from the group consisting of interferon alpha (IFN- ⁇ ), interferon beta (IFN- ⁇ ), interferon lambda (IFN- ⁇ ), and interferon gamma (IFN- ⁇ ).
  • the interferon is interferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1.
  • the interferon-alpha-2a or interferon-alpha-2b is pegylated.
  • the interferon-alpha-2a is pegylated interferon-alpha-2a (PEGASYS).
  • the additional therapeutic agent is selected from immune modulator or immune stimulator therapies, which includes biological agents belonging to the interferon class.
  • the additional therapeutic agent may be an agent of distinct or unknown mechanism including agents that disrupt the function of other essential viral protein(s) or host proteins required for HBV replication or persistence.
  • the additional therapeutic agent is an antiviral agent that blocks viral entry or maturation or targets the HBV polymerase such as nucleoside or nucleotide or non-nucleos(t)ide polymerase inhibitors.
  • the reverse transcriptase inhibitor and/or DNA and/or RNA polymerase inhibitor is Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.
  • the additional therapeutic agent is an immunomodulatory agent that induces a natural, limited immune response leading to induction of immune responses against unrelated viruses.
  • the immunomodulatory agent can effect maturation of antigen presenting cells, proliferation of T-cells and cytokine release (e.g., IL-12, IL-18, IFN-alpha, -beta, and -gamma and TNF-alpha among others).
  • the additional therapeutic agent is a TLR modulator or a TLR agonist, such as a TLR-7 agonist or TLR-9 agonist.
  • the TLR-7 agonist is selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy) adenine) and AZD 8848 (methyl [3-( ⁇ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino ⁇ methyl)phenyl]acetate).
  • the method may further comprise administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.
  • the HBV vaccine is at least one of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, or SHANVAC B.
  • provided herein is method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a compound of the invention alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of HBV vaccine.
  • the reverse transcriptase inhibitor may be one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.
  • synergistic effect may be calculated, for example, using suitable methods such as the Sigmoid-E max equation (Holford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55).
  • Sigmoid-E max equation Holford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453
  • Loewe additivity Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326
  • the median-effect equation Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55.
  • Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid
  • the method can further comprise monitoring the HBV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable.
  • composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of HBV infection in a patient.
  • compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • the dose of a compound of the invention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • a dose of a second compound is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the present invention is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of HBV infection in a patient.
  • routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • the aqueous phase was extracted with ethyl acetate (40 mL*2).
  • the combined organic phase was washed with saturated brine (30 L*2, dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction vessel was sealed and heated in microwave at 120° C. for 2 hr. LCMS showed the reaction was completed.
  • the mixture was poured into water (10 mL) and stirred for 3 min.
  • the aqueous phase was extracted with ethyl acetate (10 mL*2).
  • the combined organic phase was washed with saturated brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction vessel was sealed and heated in microwave at 130° C. for 2 hr. LCMS showed the reaction was completed.
  • the mixture was poured into water (10 mL) and stirred for 1 min.
  • the aqueous phase was extracted with ethyl acetate (10 mL*2).
  • the combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction vessel was sealed and heated in microwave at 130° C. for 2 hr. LCMS showed the reaction was completed.
  • the mixture was poured into water (10 mL) and stirred for 1 min.
  • the aqueous phase was extracted with ethyl acetate (10 mL*2).
  • the combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction vessel was sealed and heated in microwave at 145° C. for 2 hr. LCMS showed the reaction was completed.
  • the mixture was poured into water (10 mL) and stirred for 2 min.
  • the aqueous phase was extracted with ethyl acetate (10 mL*2).
  • the combined organic phase was washed with saturated brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction vessel was sealed and heated in microwave at 145° C. for 3 hr. LCMS showed the reaction was completed.
  • the mixture was poured into water (10 mL) and stirred for 2 min.
  • the aqueous phase was extracted with ethyl acetate (10 mL*2).
  • the combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction vessel was sealed and heated in microwave at 145° C. for 2 hour. LCMS showed the desired compound was detected.
  • the mixture was poured into water (10 mL) and stirred for 2 min.
  • the aqueous phase was extracted with ethyl acetate (10 mL*2).
  • the combined organic phase was washed with saturated brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction vessel was sealed and heated in microwave at 145° C. for 2 hr. LCMS showed the reaction was completed.
  • the mixture was poured into water (10 mL) and stirred for 2 min.
  • the aqueous phase was extracted with ethyl acetate (10 mL*2).
  • the combined organic phase was washed with saturated brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction vessel was sealed and heated in microwave at 110° C. for 2 hour. LCMS showed the starting material was consumed completely.
  • the mixture was poured into water (10 mL) and stirred for 2 min.
  • the aqueous phase was extracted with ethyl acetate (10 mL*2).
  • the combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • 1,2-dibromo-1,1,2,2-tetrachloro-ethane (36.84 g, 113.14 mmol, 13.59 mL, 2.00 eq) was added in one portion at ⁇ 78° C. under N 2 .
  • the mixture was stirred at 15° C. for 2.5 hr under N 2 atmosphere. TLC showed the reaction was completed.
  • the mixture was poured into ice-water (300 mL) and stirred at 5 min.
  • the aqueous phase was extracted with ethyl acetate (100 mL*3).
  • the combined organic phase was washed with brine (300 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the sealed tube was heated at 105° C. for 1 hr under microwave. LCMS showed the reaction was completed.
  • the mixture was poured into water (10 mL) and stirred at 5 min.
  • the aqueous phase was extracted with ethyl acetate (5 mL*3).
  • the combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • Oxazole-4-carboxylic acid 500.00 mg, 4.42 mmol, 1.00 eq
  • SOCl 2 10.00 mL
  • TLC indicated starting material was consumed completely.
  • the solvent was evaporated.
  • Compound oxazole-4-carbonyl chloride (570.00 mg, crude) was obtained as yellow oil. The crude product was used in the next step directly without purification.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Microbiology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
US14/984,654 2014-12-30 2015-12-30 Derivatives and methods of treating hepatitis B infections Expired - Fee Related US9550779B2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US14/984,654 US9550779B2 (en) 2014-12-30 2015-12-30 Derivatives and methods of treating hepatitis B infections
US15/375,652 US10077264B2 (en) 2014-12-30 2016-12-12 Derivatives and methods of treating hepatitis B infections
US16/024,954 US10538519B2 (en) 2014-12-30 2018-07-02 Derivatives and methods of treating hepatitis B infections
US16/702,069 US20200181142A1 (en) 2014-12-30 2019-12-03 Derivatives And Methods Of Treating Hepatitis B Infections

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201462097835P 2014-12-30 2014-12-30
US201562163150P 2015-05-18 2015-05-18
US14/984,654 US9550779B2 (en) 2014-12-30 2015-12-30 Derivatives and methods of treating hepatitis B infections

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/375,652 Continuation US10077264B2 (en) 2014-12-30 2016-12-12 Derivatives and methods of treating hepatitis B infections

Publications (2)

Publication Number Publication Date
US20160185779A1 US20160185779A1 (en) 2016-06-30
US9550779B2 true US9550779B2 (en) 2017-01-24

Family

ID=56163427

Family Applications (11)

Application Number Title Priority Date Filing Date
US14/984,654 Expired - Fee Related US9550779B2 (en) 2014-12-30 2015-12-30 Derivatives and methods of treating hepatitis B infections
US14/984,293 Expired - Fee Related US9527845B2 (en) 2014-12-30 2015-12-30 Derivatives and methods of treating hepatitis B infections
US14/984,325 Expired - Fee Related US9518057B2 (en) 2014-12-30 2015-12-30 Derivatives and methods of treating hepatitis B infections
US15/347,468 Expired - Fee Related US10093669B2 (en) 2014-12-30 2016-11-09 Derivatives and methods of treating hepatitis B infections
US15/351,851 Expired - Fee Related US9890161B2 (en) 2014-12-30 2016-11-15 Derivatives and methods of treating hepatitis B infections
US15/375,652 Expired - Fee Related US10077264B2 (en) 2014-12-30 2016-12-12 Derivatives and methods of treating hepatitis B infections
US15/843,598 Expired - Fee Related US10189835B2 (en) 2014-12-30 2017-12-15 Derivatives and methods of treating hepatitis B infections
US16/024,954 Expired - Fee Related US10538519B2 (en) 2014-12-30 2018-07-02 Derivatives and methods of treating hepatitis B infections
US16/118,760 Expired - Fee Related US10544141B2 (en) 2014-12-30 2018-08-31 Derivatives and methods of treating hepatitis B infections
US16/226,780 Expired - Fee Related US10556904B2 (en) 2014-12-30 2018-12-20 Derivatives and methods of treating hepatitis B infections
US16/702,069 Abandoned US20200181142A1 (en) 2014-12-30 2019-12-03 Derivatives And Methods Of Treating Hepatitis B Infections

Family Applications After (10)

Application Number Title Priority Date Filing Date
US14/984,293 Expired - Fee Related US9527845B2 (en) 2014-12-30 2015-12-30 Derivatives and methods of treating hepatitis B infections
US14/984,325 Expired - Fee Related US9518057B2 (en) 2014-12-30 2015-12-30 Derivatives and methods of treating hepatitis B infections
US15/347,468 Expired - Fee Related US10093669B2 (en) 2014-12-30 2016-11-09 Derivatives and methods of treating hepatitis B infections
US15/351,851 Expired - Fee Related US9890161B2 (en) 2014-12-30 2016-11-15 Derivatives and methods of treating hepatitis B infections
US15/375,652 Expired - Fee Related US10077264B2 (en) 2014-12-30 2016-12-12 Derivatives and methods of treating hepatitis B infections
US15/843,598 Expired - Fee Related US10189835B2 (en) 2014-12-30 2017-12-15 Derivatives and methods of treating hepatitis B infections
US16/024,954 Expired - Fee Related US10538519B2 (en) 2014-12-30 2018-07-02 Derivatives and methods of treating hepatitis B infections
US16/118,760 Expired - Fee Related US10544141B2 (en) 2014-12-30 2018-08-31 Derivatives and methods of treating hepatitis B infections
US16/226,780 Expired - Fee Related US10556904B2 (en) 2014-12-30 2018-12-20 Derivatives and methods of treating hepatitis B infections
US16/702,069 Abandoned US20200181142A1 (en) 2014-12-30 2019-12-03 Derivatives And Methods Of Treating Hepatitis B Infections

Country Status (10)

Country Link
US (11) US9550779B2 (enExample)
EP (1) EP3240787A4 (enExample)
JP (1) JP6713465B2 (enExample)
KR (1) KR20170118706A (enExample)
CN (1) CN107531691A (enExample)
AU (2) AU2015373996B2 (enExample)
CA (1) CA2972434A1 (enExample)
MX (1) MX383929B (enExample)
RU (1) RU2742305C2 (enExample)
WO (3) WO2016109663A2 (enExample)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170158691A1 (en) * 2014-12-30 2017-06-08 Novira Therapeutics, Inc. Derivatives And Methods Of Treating Hepatitis B Infections
US10975077B2 (en) 2016-06-29 2021-04-13 Novira Therapeutics, Inc. Diazepinone derivatives and their use in the treatment of hepatitis B infections
US10987359B2 (en) 2016-06-29 2021-04-27 Novira Therapeutics, Inc. Oxadiazepinone derivatives and methods of treating hepatitis B infections

Families Citing this family (111)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5977837B2 (ja) 2011-12-21 2016-08-24 ノヴィラ・セラピューティクス・インコーポレイテッド Ｂ型肝炎抗ウイルス剤
MX373711B (es) 2012-08-28 2020-05-08 Janssen Sciences Ireland Uc Sulfamoilarilamidas y su uso como medicamentos para el tratamiento de la hepatitis b.
DK2961732T3 (en) 2013-02-28 2017-07-10 Janssen Sciences Ireland Uc SULFAMOYLARYLAMIDS AND USE THEREOF AS MEDICINES TO TREAT HEPATITIS B
CN105102451B (zh) 2013-04-03 2018-09-18 爱尔兰詹森科学公司 N-苯基-氨甲酰衍生物及其作为药物用于治疗乙型肝炎的用途
DK2997019T3 (en) 2013-05-17 2018-12-03 Janssen Sciences Ireland Uc SULFAMOYLTHIOPHENAMIDE DERIVATIVES AND USE THEREOF AS MEDICINES FOR TREATING HEPATITIS B
JO3603B1 (ar) 2013-05-17 2020-07-05 Janssen Sciences Ireland Uc مشتقات سلفامويل بيرولاميد واستخدامها كادوية لمعالجة التهاب الكبد نوع بي
KR102244937B1 (ko) 2013-07-25 2021-04-27 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 글리옥사미드 치환된 피롤아미드 유도체 및 ｂ형 간염 치료용 의약으로서의 이의 용도
DK3060547T3 (en) 2013-10-23 2018-01-15 Janssen Sciences Ireland Uc CARBOXAMIDE DERIVATIVES AND USE THEREOF AS MEDICINES FOR TREATMENT OF HEPATITS B
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
EP3102225B1 (en) 2014-02-05 2020-03-25 Novira Therapeutics Inc. Combination therapy for treatment of hbv infections
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884831B2 (en) 2015-03-19 2018-02-06 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10738035B2 (en) 2015-05-13 2020-08-11 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2017011552A1 (en) 2015-07-13 2017-01-19 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
TW201718496A (zh) 2015-09-29 2017-06-01 諾維拉治療公司 B型肝炎抗病毒劑之晶型
CN109069488B (zh) 2016-03-07 2021-09-07 英安塔制药有限公司 乙型肝炎抗病毒剂
CN109640980A (zh) 2016-04-15 2019-04-16 诺维拉治疗公司 包含壳体装配抑制剂的组合和方法
KR20190027814A (ko) 2016-06-10 2019-03-15 이난타 파마슈티칼스, 인코포레이티드 B형 간염 항바이러스제
EP3484886B1 (en) * 2016-07-14 2020-03-04 Hoffmann-La Roche AG 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine and 6,7-dihydro-4h-triazolo[1,5-a]pyrazine compounds for the treatment of infectious diseases
WO2018011160A1 (en) * 2016-07-14 2018-01-18 F. Hoffmann-La Roche Ag 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine compounds for the treatment of infectious diseases
EP3484883B1 (en) * 2016-07-14 2020-04-15 H. Hoffnabb-La Roche Ag Novel tetrahydropyrazolopyridine compounds for the treatment of infectious diseases
JP7034133B2 (ja) * 2016-07-14 2022-03-11 エフ．ホフマン－ラ ロシュ アーゲー 感染性疾患の処置のためのカルボキシ ６，７－ジヒドロ－４Ｈ－ピラゾロ［１，５－ａ］ピラジン化合物
US10954233B2 (en) 2016-09-09 2021-03-23 Novartis Ag Compounds and compositions as inhibitors of endosomal toll-like receptors
MA46535A (fr) 2016-10-14 2019-08-21 Prec Biosciences Inc Méganucléases modifiées spécifiques de séquences de reconnaissance dans le génome du virus de l'hépatite b
TWI811236B (zh) 2017-08-28 2023-08-11 美商因那塔製藥公司 B型肝炎抗病毒試劑
AR115131A1 (es) * 2017-11-02 2020-12-02 Aicuris Gmbh & Co Kg Altamente activas indolo-2-carboxamidas sustituidas con pirazolo-pirimidina activas contra el virus de la hepatitis b (vhb)
MX2020004839A (es) * 2017-11-02 2020-10-16 Aicuris Gmbh & Co Kg Nuevas indol-2-carboxamidas sustituidas con amino-tiazol, de alta actividad, activas contra el virus de la hepatitis b (vhb).
JP7250015B2 (ja) 2017-11-16 2023-03-31 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド 抗ＨＢＶのテトラヒドロイソキサゾロ［４，３－ｃ］ピリジン類化合物
JP2021503458A (ja) * 2017-11-17 2021-02-12 ノバルティス アーゲー 新規のジヒドロイソキサゾール化合物及びｂ型肝炎治療のためのそれらの使用
WO2019113175A1 (en) 2017-12-06 2019-06-13 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
AU2018392213B2 (en) 2017-12-20 2021-03-04 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3' cyclic dinucleotides with phosphonate bond activating the STING adaptor protein
WO2019123339A1 (en) 2017-12-20 2019-06-27 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3' cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
CA3083797A1 (en) * 2017-12-21 2019-06-27 Janssen Sciences Ireland Unlimited Company Isoxazole compounds for the treatment of diseases associated with hbv infections
WO2019143902A2 (en) 2018-01-22 2019-07-25 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
JP7050165B2 (ja) 2018-02-26 2022-04-07 ギリアード サイエンシーズ， インコーポレイテッド Ｈｂｖ複製阻害剤としての置換ピロリジン化合物
JP2021515769A (ja) 2018-03-14 2021-06-24 ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー カプシド集合調節剤の投薬レジメン
WO2019191166A1 (en) * 2018-03-29 2019-10-03 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
EP3774883A1 (en) 2018-04-05 2021-02-17 Gilead Sciences, Inc. Antibodies and fragments thereof that bind hepatitis b virus protein x
TW202005654A (zh) 2018-04-06 2020-02-01 捷克科學院有機化學與生物化學研究所 ２，２，─環二核苷酸
TWI833744B (zh) 2018-04-06 2024-03-01 捷克科學院有機化學與生物化學研究所 3'3'-環二核苷酸
TWI818007B (zh) 2018-04-06 2023-10-11 捷克科學院有機化學與生物化學研究所 2'3'-環二核苷酸
TW201945388A (zh) 2018-04-12 2019-12-01 美商精密生物科學公司 對b型肝炎病毒基因體中之識別序列具有特異性之最佳化之經工程化巨核酸酶
TW202014193A (zh) 2018-05-03 2020-04-16 捷克科學院有機化學與生物化學研究所 包含碳環核苷酸之2’3’－環二核苷酸
CN110437132B (zh) * 2018-05-04 2022-04-01 上海长森药业有限公司 双并杂环核衣壳抑制剂及其药物用途
WO2020028097A1 (en) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid
US10865211B2 (en) 2018-09-21 2020-12-15 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
WO2020072955A1 (en) * 2018-10-05 2020-04-09 Emory University Monomer and multimeric anti-hbv agents
CA3117556A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
TWI721624B (zh) 2018-10-31 2021-03-11 美商基利科學股份有限公司 經取代之6-氮雜苯并咪唑化合物
AR117188A1 (es) * 2018-11-02 2021-07-21 Aicuris Gmbh & Co Kg Derivados de urea 6,7-dihidro-4h-pirazolo[1,5-a]pirazinas activas contra el virus de la hepatitis b (vhb)
UY38439A (es) 2018-11-02 2020-05-29 Aicuris Gmbh & Co Kg Novedosas urea 6,7-dihidro-4h-pirazolo[4,3-c]piridinas activas contra el virus de la hepatitis b (vhb)
UY38434A (es) 2018-11-02 2020-05-29 Aicuris Gmbh & Co Kg Nuevas 6,7-dihidro-4h-pirazolo[1,5-a]pirazin indol-2-carboxamidas activas contra el virus de la hepatitis b (hbv)
AR116948A1 (es) 2018-11-02 2021-06-30 Aicuris Gmbh & Co Kg Derivados de urea 6,7-dihidro-4h-pirazolo[1,5-a]pirazinas activas contra el virus de la hepatitis b (vhb)
EP3873913A1 (en) 2018-11-02 2021-09-08 AiCuris GmbH & Co. KG Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (hbv)
AR116947A1 (es) * 2018-11-02 2021-06-30 Aicuris Gmbh & Co Kg Derivados de urea 6,7-dihidro-4h-pirazolo[1,5-a]pirazinas-indol-2-carboxamidas activas contra el virus de la hepatitis b (vhb)
US11198693B2 (en) 2018-11-21 2021-12-14 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
CN111333590B (zh) * 2018-12-18 2022-05-17 沈阳中化农药化工研发有限公司 一种异恶唑烷盐酸盐的制备方法
MA55020A (fr) 2019-02-22 2021-12-29 Janssen Sciences Ireland Unlimited Co Dérivés d'amide utiles dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b
JP7350871B2 (ja) 2019-03-07 2023-09-26 インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー エーエスシーアール，ヴイ．ヴイ．アイ． ２’３’－環状ジヌクレオチドおよびそのプロドラッグ
WO2020178770A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides and prodrugs thereof
EP3935065A1 (en) 2019-03-07 2022-01-12 Institute of Organic Chemistry and Biochemistry ASCR, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
SG11202109575UA (en) * 2019-03-14 2021-09-29 Janssen Sciences Ireland Unlimited Co Fused ring pyrimidone derivatives for use in the treatment of hbv infection or of hbv-induced diseases
TWI751517B (zh) 2019-04-17 2022-01-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TW202210480A (zh) 2019-04-17 2022-03-16 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
CN113767101A (zh) 2019-04-30 2021-12-07 艾库里斯有限及两合公司 具有抗乙型肝炎病毒(hbv)活性的新的吲哚-2-甲酰胺类化合物
WO2020221811A1 (en) * 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel oxalyl piperazines active against the hepatitis b virus (hbv)
CN113767102A (zh) 2019-04-30 2021-12-07 艾库里斯有限及两合公司 具有抗乙型肝炎病毒(hbv)活性的新的苯基和吡啶基脲类化合物
AU2020265392A1 (en) 2019-04-30 2021-12-23 Aicuris Gmbh & Co. Kg Novel indolizine-2-carboxamides active against the hepatitis B virus (HBV)
AR119732A1 (es) 2019-05-06 2022-01-05 Janssen Sciences Ireland Unlimited Co Derivados de amida útiles en el tratamiento de la infección por vhb o de enfermedades inducidas por vhb
CN113825758B (zh) * 2019-05-14 2023-08-01 正大天晴药业集团股份有限公司 抗HBV的四氢异噁唑并[4,3-c]吡啶类化合物的晶型
EP3972695A1 (en) 2019-05-23 2022-03-30 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
UY38705A (es) * 2019-05-23 2020-12-31 Irbm S P A Inhibidores tricíclicos sustituidos con oxalamido del virus de hepatitis b
BR112021022960A2 (pt) * 2019-05-28 2022-01-04 Janssen Sciences Ireland Unlimited Co Derivados de heterociclo fundidos como moduladores da montagem do capsídeo
AU2020283774A1 (en) * 2019-05-28 2021-11-25 Janssen Sciences Ireland Unlimited Company Fused heterocyclic derivatives
CN113891890A (zh) * 2019-05-28 2022-01-04 爱尔兰詹森科学公司 氮杂卓作为hbv衣壳组装调节剂
KR20220012320A (ko) * 2019-05-28 2022-02-03 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 Hbv 캡시드 조립 조절제로서의 디플루오로 아제판
MA56043A (fr) * 2019-05-28 2022-04-06 Janssen Sciences Ireland Unlimited Co Dérivés hétérocycliques fusionnés
AU2020285719A1 (en) * 2019-05-28 2022-02-03 Janssen Sciences Ireland Unlimited Company Fused heterocyclic derivatives as antiviral agents
US11236111B2 (en) 2019-06-03 2022-02-01 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US11472808B2 (en) 2019-06-04 2022-10-18 Enanta Pharmaceuticals, Inc. Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents
WO2020247561A1 (en) 2019-06-04 2020-12-10 Enanta Pharmaceuticals, Inc, Hepatitis b antiviral agents
CN114245807B (zh) 2019-06-25 2025-05-02 吉利德科学公司 Flt3l-fc融合蛋白和使用方法
US11738019B2 (en) 2019-07-11 2023-08-29 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
WO2021023662A1 (en) * 2019-08-02 2021-02-11 Janssen Sciences Ireland Unlimited Company Pyrazolo[4,3-c]pyridine compounds for use in the treatment of hbv infection
EP4017476A1 (en) 2019-08-19 2022-06-29 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
US11236108B2 (en) 2019-09-17 2022-02-01 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
MY208114A (en) 2019-09-30 2025-04-16 Gilead Sciences Inc Hbv vaccines and methods treating hbv
CN116057068A (zh) 2019-12-06 2023-05-02 精密生物科学公司 对乙型肝炎病毒基因组中的识别序列具有特异性的优化的工程化大范围核酸酶
CN113264931B (zh) * 2020-02-17 2022-06-07 成都先导药物开发股份有限公司 一种1,4,6,7-四氢-5H-吡唑并[4,3-c]吡啶衍生物的制备方法
US11802125B2 (en) 2020-03-16 2023-10-31 Enanta Pharmaceuticals, Inc. Functionalized heterocyclic compounds as antiviral agents
WO2021188959A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
EP4126860A1 (en) * 2020-03-26 2023-02-08 Janssen Pharmaceutica NV Monoacylglycerol lipase modulators
GB202103704D0 (en) * 2021-03-17 2021-04-28 Pathios Therapeutics Ltd Compounds
MX2022015311A (es) * 2020-06-05 2023-02-22 Pathios Therapeutics Ltd N-(fenilaminocarbonil) tetrahidro-isoquinolinas y compuestos relacionados como moduladores de gpr65.
BR112023002164A2 (pt) 2020-08-07 2023-03-14 Gilead Sciences Inc Profármacos de análogos de nucleotídeos de fosfonamida e seu uso farmacêutico
TW202227435A (zh) * 2020-09-11 2022-07-16 愛爾蘭商健生科學愛爾蘭無限公司 用於治療ｈｂｖ感染或ｈｂｖ誘發的疾病之稠合環嘧啶酮衍生物
TWI815194B (zh) 2020-10-22 2023-09-11 美商基利科學股份有限公司 介白素2-Fc融合蛋白及使用方法
UY39550A (es) * 2020-12-02 2022-05-31 Janssen Sciences Ireland Unlimited Co Derivados heterocíclicos condensados
TW202348237A (zh) 2021-05-13 2023-12-16 美商基利科學股份有限公司 TLR8調節化合物及抗HBV siRNA療法之組合
AU2022298639C1 (en) 2021-06-23 2025-07-17 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
CA3222277A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
EP4359389A1 (en) 2021-06-23 2024-05-01 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
JP7686091B2 (ja) 2021-06-23 2025-05-30 ギリアード サイエンシーズ， インコーポレイテッド ジアシルグリセロールキナーゼ調節化合物
JP2024541969A (ja) 2021-10-29 2024-11-13 アーカス バイオサイエンシズ インコーポレイティド Ｈｉｆ－２アルファの阻害剤及びその使用方法
WO2025117677A1 (en) * 2023-11-29 2025-06-05 Actio Biosciences, Inc. Heterocyclic compounds useful as kcnt1 inhibitors
US20250345389A1 (en) 2024-05-13 2025-11-13 Gilead Sciences, Inc. Combination therapies
WO2025240244A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies comprising bulevirtide and lonafarnib for use in the treatment of hepatitis d virus infection
WO2025240242A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with ribavirin
WO2025240246A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with ribavirin

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014374A1 (en) 2002-07-25 2004-02-19 Pharmacia Italia S.P.A. Bicyclo-pyrazoles active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
WO2010060854A1 (en) 2008-11-25 2010-06-03 Nerviano Medical Sciences S.R.L. Bicyclic pyrazole and isoxazole derivatives as antitumor and antineurodegenerative agents
WO2012036997A1 (en) 2010-09-16 2012-03-22 Schering Corporation Fused pyrazole derivatives as novel erk inhibitors
US8273765B2 (en) 2000-08-10 2012-09-25 Pfizer Italia S.R.L. Bicyclo-pyrazoles and pharmaceutical compositions comprising them
US8288425B2 (en) 2001-10-26 2012-10-16 Aventis Pharmaceuticals Inc. Benzimidazoles
WO2014152013A1 (en) 2013-03-14 2014-09-25 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US20140330009A1 (en) 2011-09-16 2014-11-06 Sanofi Substituted 4,5,6,7-Tetrahydro-1H-Pyrazolo[4,3-C]Pyridines, Their Use as Medicament, and Pharmaceutical Preparations Comprising Them
US20160185777A1 (en) 2014-12-30 2016-06-30 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis b infections
WO2016113273A1 (en) 2015-01-16 2016-07-21 F. Hoffmann-La Roche Ag Pyrazine compounds for the treatment of infectious diseases

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK27383A (da) * 1982-02-17 1983-08-18 Lepetit Spa Fremgangsmaade til fremstilling af pyrazol(4,3-c)pyridiner
EP1309591B1 (en) * 2000-08-14 2007-01-24 Ortho-McNeil Pharmaceutical, Inc. Substituted pyrazoles
CN1642973A (zh) * 2000-09-06 2005-07-20 奥索-麦克尼尔药品公司 治疗变态反应的方法
EP1441725A1 (en) * 2001-10-26 2004-08-04 Aventis Pharmaceuticals Inc. Benzimidazoles and analogues and their use as protein kinases inhibitors
WO2003101989A1 (en) * 2002-05-30 2003-12-11 Vertex Pharmaceuticals Incorporated Inhibitors of jak and cdk2 protein kinases
US7429609B2 (en) * 2002-05-31 2008-09-30 Eisai R & D Management Co., Ltd. Pyrazole compound and medicinal composition containing the same
MXPA05000945A (es) * 2002-07-25 2005-05-16 Pharmacia Italia Spa Biciclo-pirazoles activos como inhibidores de la cinasa, procedimientos para su preparacion y composiciones farmaceuticas que los contienen.
AU2004276341B2 (en) * 2003-09-23 2011-04-14 Vertex Pharmaceuticals Incorporated Pyrazolopyrrole derivatives as protein kinase inhibitors
KR20090024834A (ko) 2006-07-05 2009-03-09 인터뮨, 인크. Ｃ형 간염 바이러스 복제의 신규 억제제
WO2009158394A1 (en) * 2008-06-25 2009-12-30 Bristol-Myers Squibb Company Diketo azolopiperidines and azolopiperazines as anti-hiv agents
KR101787116B1 (ko) * 2009-01-28 2017-10-18 케러 테라퓨틱스, 인코포레이티드 바이시클릭 피라졸로-헤테로사이클
WO2011019842A1 (en) * 2009-08-12 2011-02-17 Janssen Pharmaceutica Nv Process for the preparation of cathepsin s inhibitors
US20130178475A1 (en) * 2010-03-17 2013-07-11 Ironwood Pharmaceuticals, Inc. sGC STIMULATORS
US9351965B2 (en) * 2010-12-21 2016-05-31 Merck Sharp & Dohme Corp. Indazole derivatives useful as ERK inhibitors
KR101316101B1 (ko) * 2011-05-26 2013-10-11 연세대학교 산학협력단 Ｐｔｋ 6의 활성 억제용 조성물 및 이를 이용한 암 예방 및 치료용 조성물
JP5893143B2 (ja) * 2011-09-12 2016-03-23 サノフイ インダニル置換の４，５，６，７−テトラヒドロ−１Ｈ−ピラゾロ［４，３−ｃ］ピリジン、医薬としてのその使用、及びそれらを含む医薬製剤
MX2014003181A (es) * 2011-09-16 2015-08-05 Sanofi Sa 4,5,6,7-tetrahidro-1h-pirazolo [4,3-c] piridinas sustituidas, su uso como medicamento y preparaciones farmacéuticas que las comprenden.

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8273765B2 (en) 2000-08-10 2012-09-25 Pfizer Italia S.R.L. Bicyclo-pyrazoles and pharmaceutical compositions comprising them
US8288425B2 (en) 2001-10-26 2012-10-16 Aventis Pharmaceuticals Inc. Benzimidazoles
WO2004014374A1 (en) 2002-07-25 2004-02-19 Pharmacia Italia S.P.A. Bicyclo-pyrazoles active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
WO2010060854A1 (en) 2008-11-25 2010-06-03 Nerviano Medical Sciences S.R.L. Bicyclic pyrazole and isoxazole derivatives as antitumor and antineurodegenerative agents
WO2012036997A1 (en) 2010-09-16 2012-03-22 Schering Corporation Fused pyrazole derivatives as novel erk inhibitors
US9242981B2 (en) * 2010-09-16 2016-01-26 Merck Sharp & Dohme Corp. Fused pyrazole derivatives as novel ERK inhibitors
US20140330009A1 (en) 2011-09-16 2014-11-06 Sanofi Substituted 4,5,6,7-Tetrahydro-1H-Pyrazolo[4,3-C]Pyridines, Their Use as Medicament, and Pharmaceutical Preparations Comprising Them
WO2014152013A1 (en) 2013-03-14 2014-09-25 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US20160185777A1 (en) 2014-12-30 2016-06-30 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis b infections
US20160185778A1 (en) 2014-12-30 2016-06-30 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis b infections
WO2016109684A2 (en) 2014-12-30 2016-07-07 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis b infections
WO2016109663A2 (en) 2014-12-30 2016-07-07 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis b infections
WO2016109689A2 (en) 2014-12-30 2016-07-07 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis b infections
WO2016113273A1 (en) 2015-01-16 2016-07-21 F. Hoffmann-La Roche Ag Pyrazine compounds for the treatment of infectious diseases

Non-Patent Citations (63)

* Cited by examiner, † Cited by third party
Title
International Search Report with Written Opinion corresponding to International Patent Application No. PCT/US2015/068059, mailed Jun. 29, 2016.
International Search Report with Written Opinion corresponding to International Patent Application No. PCT/US2015/068091, mailed Jun. 29, 2016.
International Search Report with Written Opinion corresponding to International Patent Application No. PCT/US2015/068099, mailed Jun. 29, 2016.
Samala et al. (Sep. 12, 2013) "Development of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pridine derivatives as novel Mycobacterium tuberculosis pantothenate synthetase inhibitors," Eur. J. Med. Chem. 9:356-364.
SciFinder Database. CAS Registration No. 1061115-87-4. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1067040-18-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1069950-13-5. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1070212-99-5. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1070291-29-0. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1087421-81-5. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1087511-95-2. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1087555-42-7. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1172227-82-5. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1172868-89-1. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1279839-42-7. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1279878-41-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1279879-10-5. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1279891-91-6. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1279891-93-8. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1331941-88-8. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1332163-49-1. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1332212-51-7. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1333648-57-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1333801-98-1. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1333912-79-0. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1340862-20-5. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1340896-72-1. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1341016-11-2. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1355539-18-2. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1355607-29-2. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1355640-11-7. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1355842-55-5. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1355890-97-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1360376-35-7. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1368359-39-0. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1369082-23-4. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1497548-79-4. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1497623-25-2. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1497669-55-2. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1501166-65-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1511831-42-7. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1516653-16-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1522224-86-7. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1567296-86-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1567311-64-1. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1567490-89-4. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1574576-07-0. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1574592-26-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1574626-86-0. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1574640-97-3. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 1609742-77-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 895821-52-0. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 895828-24-7. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 895835-76-4. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 895842-18-9. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 899378-47-3. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 903199-10-0. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 903585-33-1. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 903853-89-4. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 903867-06-1. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 903867-67-4. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 906757-81-1. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].
SciFinder Database. CAS Registration No. 906762-37-6. Chemical Abstract Services. American Chemical Society. [Last Accessed Jul. 25, 2016].

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170158691A1 (en) * 2014-12-30 2017-06-08 Novira Therapeutics, Inc. Derivatives And Methods Of Treating Hepatitis B Infections
US9890161B2 (en) 2014-12-30 2018-02-13 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis B infections
US10077264B2 (en) * 2014-12-30 2018-09-18 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis B infections
US10093669B2 (en) 2014-12-30 2018-10-09 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis B infections
US10189835B2 (en) 2014-12-30 2019-01-29 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis B infections
US10538519B2 (en) 2014-12-30 2020-01-21 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis B infections
US10544141B2 (en) 2014-12-30 2020-01-28 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis B infections
US10556904B2 (en) 2014-12-30 2020-02-11 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis B infections
US10975077B2 (en) 2016-06-29 2021-04-13 Novira Therapeutics, Inc. Diazepinone derivatives and their use in the treatment of hepatitis B infections
US10987359B2 (en) 2016-06-29 2021-04-27 Novira Therapeutics, Inc. Oxadiazepinone derivatives and methods of treating hepatitis B infections

Also Published As

Publication number Publication date
US10544141B2 (en) 2020-01-28
WO2016109689A2 (en) 2016-07-07
AU2015373996B2 (en) 2020-10-08
US20170158691A1 (en) 2017-06-08
KR20170118706A (ko) 2017-10-25
US9518057B2 (en) 2016-12-13
US20170121329A1 (en) 2017-05-04
AU2015373996A1 (en) 2017-07-13
MX383929B (es) 2025-03-14
MX2017008720A (es) 2018-01-25
EP3240787A4 (en) 2018-06-20
RU2017126995A3 (enExample) 2019-04-22
AU2020233640A1 (en) 2020-10-08
WO2016109663A2 (en) 2016-07-07
CN107531691A (zh) 2018-01-02
JP2018500372A (ja) 2018-01-11
WO2016109689A3 (en) 2016-08-25
US10556904B2 (en) 2020-02-11
US10189835B2 (en) 2019-01-29
US9527845B2 (en) 2016-12-27
RU2017126995A (ru) 2019-01-31
US20160185778A1 (en) 2016-06-30
US20190031653A1 (en) 2019-01-31
US20200181142A1 (en) 2020-06-11
CA2972434A1 (en) 2016-07-07
US10093669B2 (en) 2018-10-09
WO2016109663A3 (en) 2016-10-13
RU2742305C2 (ru) 2021-02-04
US20170121328A1 (en) 2017-05-04
US10538519B2 (en) 2020-01-21
WO2016109684A3 (en) 2016-08-25
US10077264B2 (en) 2018-09-18
EP3240787A2 (en) 2017-11-08
US9890161B2 (en) 2018-02-13
WO2016109684A2 (en) 2016-07-07
JP6713465B2 (ja) 2020-06-24
US20190077800A1 (en) 2019-03-14
US20180127415A1 (en) 2018-05-10
US20160185779A1 (en) 2016-06-30
US20190194191A1 (en) 2019-06-27
US20160185777A1 (en) 2016-06-30

Similar Documents

Publication Publication Date Title
US10538519B2 (en) Derivatives and methods of treating hepatitis B infections
US20210252014A1 (en) Oxadiazepinone derivatives and methods of treating hepatitis b infections
US10364228B2 (en) Azepane derivatives and methods of treating hepatitis B infections
US9400280B2 (en) Piperidine derivatives and methods of treating hepatitis B infections
US9339510B2 (en) Azepane derivatives and methods of treating hepatitis B infections
US20170015629A1 (en) Azepane derivatives and methods of treating hepatitis b infections
US20210220356A1 (en) Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases
US20220348571A1 (en) Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVIRA THERAPEUTICS, INC., PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HARTMAN, GEORGE D.;KUDUK, SCOTT;REEL/FRAME:037911/0874

Effective date: 20160106

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20250124